In mammals, triglycerides are stored in adipose tissue providing the primary source of energy during periods of food deprivation. Whole body energy homeostasis depends on the precisely regulated balance of lipid storage and mobilization. White adipose tissue (WAT) functions as buffer for dietary lipids and stores excess energy in the form of triacylglycerol (TG). Mobilization of fatty acids from TG stores in adipose tissue critically depends on the activation of lipolytic enzymes. Upon demand, TG stores are hydrolyzed by lipolytic enzymes and the body is provided with free fatty acids (FA) for energy conversion or for the synthesis of complex lipids. Efficient lipolysis requires a three-step process involving three enzymes: Adipose triglyceride lipase (ATGL, also annotated as patatin-like phospholipase domain containing 2, desnutrin, phospholipase A2zeta, and transport secretion protein 2.2), hormone-sensitive lipase (HSL), and monoglyceride lipase (MGL). ATGL removes the first fatty acid from the TG molecule and generates diacylglycerol (DG). HSL is the rate-limiting enzyme for the hydrolysis of DG and MGL performs the last step in this reaction leading to the liberation of FA and glycerol.
FA mobilization in WAT and non-adipose tissues is strongly dependent on ATGL and its co-activator protein CGI-58 (comparative gene expression 58, also known as α/β hydrolase fold-containing 5). In humans, loss-of-function mutations in either of these genes are associated with Neutral Lipid Storage Disease (NLSD), a rare autosomal recessive disorders characterized by the excessive accumulation of neutral lipids in multiple tissues. Similarly as observed in humans, a complete absence of ATGL function in mice is associated with severely reduced lipolysis, obesity, and fat deposition in virtually all tissues of the body. Under fasting conditions, ATGL-deficient animals are unable to mobilize sufficient energy in the form of FA to maintain normal energy homeostasis. Prolonged starvation induces a torpor-like metabolic state characterized by decreased plasma FA concentrations, hypoglycemia, reduced oxygen consumption, and hypothermia. It has been observed that increased circulating FA concentrations, as seen in obesity, can promote fat deposition, insulin resistance, and inflammation in non-adipose tissues. These adverse effects of ectopic lipid overload are known under the term “lipotoxicity” and central in the pathogenesis of metabolic disorders.
Dysfunctional lipolysis affects energy homeostasis and may contribute to the pathogenesis of obesity and insulin resistance. Dysregulation of TG-lipolysis in man has been linked to variations in the concentration of circulating FA, an established risk factor for the development of insulin resistance (Bergman, R. N. et al (2001) J Investig Med 49: 119-26; Blaak, E. E. (2003) Proc Nutr Soc 62: 753-60; Boden, G. and G. I. Shulman (2002) Eur J Clin Invest 32(Suppl 3):14-23; Arner, P. (2002) Diabetes Metab Res Rev 18(Suppl 2): S5-9).
During periods of increased energy demand, lipolysis in adipocytes is activated by hormones, such as catecholamines. Hormone interaction with G-protein coupled receptors is followed by increased adenylate cyclase activity, increased cAMP levels, and the activation of cAMP-dependent protein kinase (protein kinase A, PKA) (Collins, S. and R. S. Surwit (2001) Recent Prog Horm Res 56:309-28). PKA then phosphorylates targets with established function in lipolysis including hormone-sensitive lipase (HSL), resulting in the translocation of HSL from the cytoplasm to the lipid droplet where efficient TG hydrolysis occurs (Sztalryd, C. et al (2003) J Cell Biol 161:1093-103).
The mobilization of free fatty acids from adipose triacylglycerol (TG) stores requires the activities of triacylglycerol hydrolases. Adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) are the major enzymes contributing to TG breakdown. ATGL (also named PNPLA 2 (patatin-like phospholipase domain containing protein-2, desnutrin, phospholipase A2δ, and transport-secretion protein)) is highly expressed in adipose tissue and specifically removes the first fatty acid from the TG molecule, generating FFA and DG (Zimmermann, R. et al (2004) Science 306:1383-1386; Wang, S P et al (2001) Obes Res 9:119-128; Villena, J A et al (2004) J Biol Chem 279:47066-47075; Jenkins, C M et al (2004) J Biol Chem 279:48968-48975). An essential role of ATGL in lipolypsis has been demonstrated in studies of ATGL-deficient (ATGL-ko) mice (Haemmerle, G. et al (2006) Science 312:734-737). ATGL-deficient mice accumulated large amounts of lipid in the heart, causing cardiac dysfunction and premature death. The relative contribution of these hydrolases to the lipolytic catabolism of fat has been determined, in mutant mouse models lacking ATGL or HSL (Schweiger, M. et al (2006) J Biol Chem 281(52):40236-40241). Both HSL and ATGL enzymes contribute to hydrolysis of TG, however, ATGL deficient mice studies indicate that ATGL is rate limiting in the catabolism of cellular fat deposits and plays an important role in energy homeostasis (Haemmerle, G. et al (2006) Science 312(5774):734-737).
Cachexia is a life-threatening syndrome characterized by the unattended loss of body weight, muscle atrophy, fatigue, weakness and significant loss of appetite in someone who is not actively trying to lose weight. It can be a sign of various underlying disorders. It occurs in about 50% of cancer patients but is also observed in other diseases including certain infectious diseases (e.g. tuberculosis, AIDS), in or alcoholchronic obstructive pulmonary disease, and advanced organ failure (liver, heart, kidney). Cachexia physically weakens patients to a state of immobility stemming from loss of appetite, asthenia, and anemia, and response to standard treatment is usually poor (Lainscak M, et al (2007) Curr Opin Support Palliat Care 1(4): 299-305; Bossola M et al (2007) Expert Opin Investig Drugs 16 (8): 1241-53). Recently, is has been shown that lipolysis is also increased in cancer associated cachexia, leading to a loss of adipose tissue (Thompson et al). Another study provided evidence that ATGL deficiency protects from cancer cachexia associated loss of adipose tissue and skeletal muscle (Das, 2011). Thus, inhibiting ATGL might provide a novel medical intervention technique to prevent the loss of adipose and skeletal muscle mass in cancer cachexia. This could prevent uncontrolled weight loss and increase life expectancy of cancer patients.
Cachexia is also prevalent in HIV patients before the advent of highly active anti-retroviral therapy (HAART) and in patients that have any of the range of illnesses classified as “COPD” (chronic obstructive pulmonary disease), particularly emphysema. Some severe cases of schizophrenia can present this condition where it is named vesanic cachexia (from vesania, a Latin term for insanity). Metabolic syndrome is a name for a group of risk factors that occur together and increase the risk for coronary artery disease, stroke, and type 2 diabetes. All of the risks for the syndrome are related to obesity. The two most important risk factors for metabolic syndrome are: Extra weight around the middle and upper parts of the body (central obesity), and insulin resistance. As a result, blood glucose and fat levels rise. Other risk factors include lack of exercise and age. Metabolic syndrome is associated with dyslipidemia and especially increased plasma levels of FA may have a causal role in the development of the syndrome.
Moreover, increased blood levels of FA are also a risk factor for the development of atherosclerosis, stroke, and coronary artery disease. To prevent or treat disorders caused by dyslipidemia, an effective tool represents may be the effective reduction of excessive blood FA levels.